4-benzyloxy-3-pyrrolin-2-on-1-yl acetamide production

ABSTRACT

4-Benzyloxy-3-pyrrolin-2-on-1-yl acetamide is an advantageous intermediate product for the production of pharmaceutically effective 4-hydroxypyrrolidin-2-1-yl acetamide. Processes for the production of the intermediate product as well as the active substance are described.

This is a divisional of Application Ser. No. 060,262, filed on June 10,1987.

BACKGROUND OF THE INVENTION

1. Field Of The Invention

The new 4-benzyloxy-3-pyrrolin-2-on-1-yl acetamide is a valuableintermediate product for the synthesis of cerebrally effective4-hydroxypyrrolidin-2-on-1-yl acetamide (oxiracetam).

2. Background Art

A process is known from Pifferi et al., Il Farmaco, Ed. Sc., 1977, 32,602, for producing the active substance. But a poor yield and expensiveinitial products make the process unprofitable.

BROAD DESCRIPTION OF THE INVENTION

The main object of the invention is to provide a production processwhich does not have such disadvantages.

This object was able to be attained in a remarkably simple way by thediscovery of the new intermediate 4-benzyloxy-3-pyrrolin-2-on-1-ylacetamide. This intermediate material can be reached either from a 4-(C₁-C₂)-alkoxy-3-pyrrolin-2-one or a 4-(C₁ -C₂)-alkoxy-3-pyrrolin-2-on-1-ylacetic acid-(C₁ -C₄) alkyl ester. More specifically,4-benzyloxy-3-pyrrolin-2-on-1-yl acetamide of the formula: ##STR1## isproduced by either transesterification of a 4-(C₁-C₂)-alkoxy-3-pyrrolin-2-one with benzyl alcohol in the presence of anacid to 4-benzyloxy-3-pyrrolin-2-one, alkylation with 2-bromoaceticacid-(C₁ -C₄) alkyl ester in the presence of an alkali hyride to4-benzyloxy-3-pyrrolin-2-on-1-yl acetic acid (C₁ -C₄) alkyl ester andfinally conversion with ammonia to the end product, or conversion of a4-(C₁ -C₂) alkoxy-3-pyrrolin-2-on-1-yl acetic acid (C₁ -C₄) alkyl esterwith benzyl alcohol in the presence of an acid to4-benzyloxy-3-pyrrolin-2-on-1-yl acetic acid benzyl ester and,optionally without its isolation, with ammonia to the end product.

Initial products with longer alkoxy or alkyl groups can easily be used.But since these groups are again split off in the course of the process,such compounds are of no significant interest.

Starting from 4-(C₁ -C₂)-alkoxy-3-pyrrolin2-one conversion to4-benzyloxy-3-pyrroline-2-one is performed in a first step in thepresence of an acid with benzyl alcohol. As acids for this step,sulfonic acids, such as, methane sulfonic acid or p-toluene sulfonicacid, are suitably used in catalytic amounts of suitably 0.05 to 0.2mol. It is advantageous to operate directly in benzyl alcohol as thesolvent. Benzyl alcohol is suitably used in an amount of 1.5 to 5 molper mol of initial product.

The reaction temperature is advantageously in the range of 60° to 100°C. Since in this reaction a transesterification is involved, it isadvantageous to perform the reaction at reduced pressure between 10 and50 mbars to remove from the equilibrium the low-boiling alcohols thathave split off.

After the completed reaction, i.e., after about 10 to 25 hours(depending on the catalyst amount of sulfonic acid), the4-benzyloxy-3-pyrrolin-2-one can be worked up in a usual way, e.g., byazeotropic separation of the excess benzyl alcohol and optionally bycrystallization of the resulting product.

in a second step the resultant product is converted with a bromoaceticacid (C₁ -C₄) alkyl ester in the presence of an alkali hydride to4-benzyloxy3-pyrrolin-2-on-1-yl acetic acid-(C₁ -C₄) alkyl ester.Bromoacetic acid ethyl ester in an amount of suitably 1 to 1.5 mol permol of 4-benzyloxy-3-pyrrolin-2-one is used as the preferred bromoaceticacid alkyl ester. Sodium hydride is used as the preferred alkali hydridein an amount of 1 to 1.5 mol per mol of the4-benzyloxy-3-pyrrolin-2-one.

Advantageously, the operation is performed in a polar, aprotic solvent,such as dimethylformamide, dimethyl acetamide and acetonitrile,(especially advantageously in acetonitrile as the solvent, at a reactiontemperature of 0° to 40° C.

The resultant 4-benzyloxy-3-pyrrolin-2-on-1-yl acetic acid-(C₁ -C₄)alkyl ester can be converted in a last stage with ammonia to4-benzyloxy-3-pyrrolin-2-on-1-yl acetamide. Suitably in this case theprocedure is such that the initial product is advantageously dissolvedin an alcohol, such as methanol or ethanol, the alcohol being previouslysaturated with gaseous ammonia at -10° to 0° C., and then the reactionmixture is stirred in an autoclave at 60° to 80° C. for 10 to 15 hours.

After the usual work-up, the desired intermediate product can beobtained in good yield and quality.

If the start is made from 4-(C₁ -C₄)-alkoxy-3-pyrrolin-2-on-1-yl aceticacid (C₁ -C₄) alkyl ester, a conversion is performed in a first stepwith benzyl alcohol, in an acid manner to4-benzyloxy-3-pyrrolin-2-on-1-yl acetic acid benzyl ester. As acids forthis step, suitably sulfonic acids, preferably methane sulfonic acid orp-toluene sulfonic acid, in catalytic amounts of suitably 0.05 to 0.2mol are used.

It is advantageous to work directly in benzyl alcohol as the solvent.The benzyl alcohol is suitably used in an amount of 2.5 to 5.0 mol permole of initial product. The reaction temperature is advantageously inthe range of 80° to 120° C. As in the production of4-benzyloxy-3-pyrrolin-2-one, it is advantageous to perform the reactionat reduced pressure, preferably between 10 to 50 mbars.

After reaction is completed, i.e., after about 7 to 10 hours,4-benzyloxy-3-pyrrolin-2-on-1-yl acetic acid benzyl ester can beobtained after the usual work-up and optionally by purification by meansof recrystallization.

In a last step, conversion with ammonia to the desired intermediateproduct to 4-benzyloxy-3-pyrrolin-2-on-1-yl acetamide can then beperformed. Advantageously the alcohol, preferably methanol and ethanol,functioning as solvent for this purpose is saturated with gaseousammonia at -10° to 0° C., then the 4-benzyloxy-3-pyrrolin-2-on-1-ylacetic acid benzyl ester is added and finally the reaction mixture isstirred in the autoclave at 60° to 80° C. for 6 to 10 hours.

After a simple work-up, the desired intermediate product can be obtainedin good yield and quality.

The 4-benzyloxy-3-pyrrolin-2-on-1-yl acetamide can be used as anespecially advantageous intermediate product for production ofcerebrally effective 4-hydroxypyrrolidin-2-on-1-yl acetamide.

Suitably for this purpose catalytic hydrogenation is performed in afirst step.

Noble metal catalysts are suitably used as catalysts, which causes aselective debenzylation. Preferably palladium, applied to a usualsupport material, preferably on activated carbon, with a catalystcontent of 1 to 10 percent is used. The catalyst amount suitably rangesbetween 5 and 10 percent by weight, in relation to the amount of4-benzyloxy-3-pyrrolin-2-on-1-yl acetamide used.

The intermediately resultant 2,4-dioxopyrrolidin-1-yl acetamide can bereduced with complex borohydrides, preferably with alkali borohydrides,especially preferably with sodium borohydride, to the end product. Thus,it is advantageous to perform the debenzylation in a polar aproticsolution, such as, dimethylformamide or dimethyl acetamide, under apressure of suitably 1 to 20 bars and at a temperature suitably between0° and 30° C. The alkali borohydride is preferably used in an amount of0.5 to 0.8 mol per mol of 4-benzyloxy-3-pyrrolin-2-on-1-yl acetamide.

While maintaining the polar aprotic solvent, the operation is suitablyperformed at a temperature of 0° to 30° C. In this way, a correspondingadvantage of the process described here applies, because the sensitive2,4-dioxopyrrolidin-1-yl acetamide tending to dimerization is kept insolution and must not be isolated, whichever, is possible.

If catalytic hydrogenation is selected for conversion of theintermediate 2,4-dioxopyrrolidin-1-yl acetamide to the end product,advantageously the operation for the catalytic hydrogenolysis isperformed in a polar protic anhydrous solvent, such as, methanol,ethanol or acetic acid, at suitably 1 to 20 bars and a temperature ofsuitably 0° to 30° C. The catalyst and catalyst amount advantageouslyremain unchanged with respect to the catalytic hydrogenolysis in polaraprotic solvents.

The catalytic hydrogenation is then suitably performed with platinumcatalysts, such as platinum oxide or platinum, applied in an amount of 1to 10 percent to a support, preferably to activated carbon.

The catalyst amount suitably ranges between 1 and 10 percent by weightin relation to the 4-benzyloxy-3-pyrrolin-2-on-1-yl acetamide. Thehydrogen pressure suitably is between 5 to 20 bars, the temperature isbetween 0° and 30° C. Also in this catalytic reduction it isadvantageous to keep the intermediately formed 2,4-dioxopyrrolidin-1-ylacetamide in solution and not to isolate it.

It is especially preferable to perform the debenzylation of the4-benzyloxy-3-pyrrolin-2-on-1-yl acetamide by catalytic hydrogenolysisand the catalytic reduction by hydrogenation of the intermediate2,4-dioxopyrrolidin-1-yl acetamide with hydrogen as a one-pot processwith palladium/platinum mixed catalysts. Again the polar aproticanhydrous solvents, such as, methanol, ethanol or anhydrous acetic acid,are suitably used. The hydrogen pressure ranges advantageously between 5and 20 bars and the temperature between 0° and 30° C. Suitably apalladium/platinum mixed catalyst is used, whose palladium to platinumratio is 5 to 1 to 1 to 2. The palladium portion is preferably used inan amount of 1 to 10 percent, applied to a usual support, preferably toactivated carbon. The platinum portion can be present as platinum oxideor also as platinum, applied in an amount of 1 to 10 percent to a usualsupport, preferably to activated carbon. The mixed catalyst is used inan amount of suitably 5 to 15 percent by weight, in relation to the4-benzyloxy-3-pyrrolin-2-on-1-yl acetamide.

The work-up of the end product, independently of which process isselected, can take place in a usual process manner. The resultant4-hydroxypyrrolidin-2-on-1-yl acetamide can optionally be purified byrecrystallization.

Via the new 4-benxyloxy-3-pyrrolin-2-on-1-yl acetamide as a newintermediate product and with the help of the process according to theinvention, one can in the described way produce4-hydroxy-3-pyrrolidin2-on-1-yl acetamide in good yields and in puritiesgreater than 98 percent.

DETAILED DESCRIPTION OF THE INVENTION EXAMPLE 1

(a) Production of 4-benzyloxy-3-pyrrolin-2-on-1-yl acetic acid benzylester

20.8 g of 4-methoxy-3-pyrrolin-2-1-yl acetic acid ethyl ester wasdissolved in 44.1 g of benzyl alcohol, mixed with 1.0 g of methanesulfonic acid and stirred at 80° C. and 20 mbars for 12 hours. Then thereaction solution was mixed with 250 ml of methylene chloride and 500 mlof ice water, and neutralized with 10 ml of saturated NaHCO₃ solution.After drying of the organic phase over Na₂ SO₄ and evaporation of thesolvent, the residue was mixed with 400 ml of a 2:1 mixture of ice waterand ethanol. As a result the product crystallized out. The yield was25.8 g (76 percent). TLC showed no byproducts. The melting point of theproduct was 92° to 94° C. For the product:

NMR: (300 MHz, CDCl ₃) δ in ppm, 7.45-7.29 (m, 10H), 5.20 (s, 1H), 5.16(s, 2H), 4.98 (s, 2H), 4.22 (s, 2H), 4.03 (s, 2H).

MS (70 eV): 337 (M⁺, 2), 246 (7), 202 (14), 145 (10), 91 (100), 65 (12).

(b) Production of 4-benzyloxy-3-pyrrolin-2-on-1-yl acetamide

25.0 g of 4-benzyloxy-3-pyrrolin-2-on-1-yl acetic acid benzyl ester wasdissolved in 500 ml of methanol and stirred at 40° C. with passing ofgaseous NH₃ for 5 hours. Then the reaction solution was evaporated andthe residue was mixed with 50 ml of acetone. The precipitated crystalswere filtered by suction and dried. 15.2 g of TLC pure product with amelting point of 174.5 to 175.5° C. was obtained. For the product:

NMR: (300 MHz, MDSO-d₆) δ in ppm, 7.50-7.32 (m, 6H), 7.05 (br. s, 1H),5.27 (s, 1H), 5.06 (s, 2H), 4.20 (s, 2H), 3.85 (s, 2H).

MS: (70 eV): 246 (M⁺ m, 20), 229 (23), 202 (49), 145 (30), 91 (100), 65(52).

EXAMPLE 2

(a) Direct production of 4-benzyloxy-3-pyrrolin-2-on-1-yl acetamide from4-methoxy-3-pyrrolin-2-on-1-yl acetic acid methyl ester 25.0 g (0.132mol) of 4-methoxy-3-pyrrolin-2-on-1-yl acetic acid methyl ester (98.0percent), 41.7 g (0.38 mol) of benzyl alcohol and 1.9 g (19.8 mmol) ofmethane sulfonic acid were stirred for 8 hours at 110° C. in a water jetvacuum at 20 mbars. Then diluting with 167 ml of methylene chloride andmixing with 84 ml of ice water were performed. The aqueous phase wasneutralized with 19.8 ml of saturated NaHCO₃ solution and extractedtwice with 70 ml each of methylene chloride. The organic phases werecombined, dried over Na₂ SO₄ and concentrated in the rotary evaporator.The residue (57.7 g) was added to a methanol solution (34 ml) saturatedwith gaseous NH₃ at -10° C. and stirred in the autoclave at 70° to 80°C. for 9 hours. Then the methanol was evaporated, the residue mixed with100 ml of carbon tetrachloride, cooled to 5° C. and the precipitatedcrystals were filtered by suction. The raw product (32.0 g) wasrecrystallized hot from 31 ml of water. 26.3 g of nearly white productwith a content after HPLC of 97.9 percent was obtained. The yield was79.4 percent.

EXAMPLE 3

(a) Production of 4-benzyloxy-3-pyrrolin-2-one 5.7 g of4-methoxy-3-pyrrolin-2-one and 10.8 g of benzyl alcohol were mixed with0.4 g of methane sulfonic acid and stirred for 24 hours at 80° C. and 20mbars. Then the reaction solution was mixed with 50 ml of ice water and100 ml of methylene chloride and neutralized with 4 ml of saturatedNaHCO₃ solution. The aqueous phase was extracted twice more with 50 mleach of methylene chloride. After drying of the organic phase over Na₂SO₄ and distilling off of the solvent, the residue was mixed with 150 mlof ice water, heated to 100° C. and 100 ml of water-benzyl alcohol wasazeotropically distilled off. The crystals precipitated during thecooling were recrystallized hot from 50 ml of toluene. 6.7 g of white,crystalline product with a melting point of 147° to 148° was obtained.For the product:

NMR: (300 MHz, DMSO=d₆), 7.38 (m, 5H), 6.20 (br. s, 1H), 5.16 (s, 1H),4.98 (s, 2H), 3.98 (s, 2H).

MS: (70 eV): 189 (m⁺, 40), 172 (18), 132 (51), 91 (100).

(b) Production of 4-benzyloxy-3-pyrrolin-2-on-1-yl acetamide from4-benzyloxy-3-pyrrolin-2-one 8.4 g of 4-benzyloxy-3-pyrrolin-2-one and9.8g of bromoacetic acid ethyl ester (95 percent) were dissolved in 50ml of anhydrous acetonitrile and cooled to 0° C. To this reactionsolution was added within 20 minutes 1.67 g of sodium hydride (80percent in white oil). Additional stirring for 2 hours was performed,acidification was performed with concentrated hydrochloric acid to pH 6to 7 and the solvent was distilled off. The residue was taken up inwater/methylene chloride. After separation of the organic phase, 14.4 gof raw product was obtained. This raw product was dissolved in 20 ml ofmethanol, which was previously saturated with gaseous ammonia at -10° to0° C. The reaction solution was stirred in the autoclave for 12 hours at60° to 80° C. After distilling off of the methanol and washing of theraw product with carbon tetrachloride, recrystallization from water wasperformed. 5.1 g of TLC pure product was obtained.

EXAMPLE 4

Catalytic hydrogenolysis and hydrogenation of4-benzyloxy-3-pyrrolin-2-on-1-yl acetamide 3.00 g of4-benzyloxy-3-pyrrolin-2-on-1-yl acetamide was dissolved in 30 ml ofconcentrated acetic acid and mixed with 240 mg of palladium 5 percent onactivated carbon and 24 mg of platinum oxide. Hydrogenolysis andhydrogenation at 15 bars of hydrogen pressure and room temperature wereperformed for 65 hours. Then filtering off from the catalyst andevaporation of the solvent were performed. The residue was picked up inH₂ O and allowed to run over 5.0 g of weakly basic ion exchanger. Thewater was distilled off and the residue mixed with 10 ml of acetone.1.53 g of nearly white 4-hydroxypyrrolidin-2-on-1-yl acetamide with amelting point of 163.5° to 165.7° C. was obtained.

EXAMPLE 5

Hydrogenolysis and NaBH₄ reduction of 4-benzyloxy-3-pyrrolin-2-on-1-ylacetamide 10.0 g of 4-benzyloxy-3-pyrrolin-2-on-1-yl acetamide washydrogenolyzed in 33 ml of dimethylformamide in the presence of 800 mgof palladium 5 percent on activated carbon at an H₂ pressure of 20 barsand at room temperature for 5 hours. Then the catalyst was filtered offand the filtrate was instilled within an hour at room temperature into asolution of 1.1 g of sodium boron hydride in 17 ml of dimethylformamide.Two additional hours of stirring was performed and the reaction solutionwas acidified with 3 ml of 1 to 1 mixture of formic acid and methanol.The solvents were distilled off. The residue was taken up in 100 ml ofice water, after that it was filtered over 80 g of strongly acidic ionexchanger and then over 80 g of weakly basic ion exchanger. The aqueoussolution was evaporated and the residue taken up in 70 ml of methanol.50 ml of methanol was distilled off, with the 4-hydroxypyrrolidin-2-1-ylacetamide precipitating as microcrystalline pecipitate. 4.2 g of productwith a melting point of 166.2° to 167.3° C. (HPLC content 96.9 percent)was obtained.

Recrystallization from acetic acid/acetone in a ratio of 1 to 3 yieldeda product with a melting point of 168° to 169.5° C. and an HPLC contentof 99.0 percent.

What is claimed is:
 1. Process for the production of4-Benzyloxy-3-pyrrolin-2-on-1-yl acetamide of the formula: ##STR2##Comprising transetherifying a 4-(C₁ -C₂)-alkoxy-3-pyrrolin-2-one withbenzyl alcohol in the presence of an acid to4-benzyloxy-3-pyrrolin-2-one, alkylating the transetherified compoundwith 2-bromoacetic acid-(C₁ -C₄) alkyl ester in the presence of analkali hydride to 4-benzyloxy-3-pyrrolin-2-on-1-yl acetic acid (C₁ -C₄)alkyl ester, and converting the alkylated compound with ammonia to theend product.
 2. Process according to claim 1 wherein a sulfonic acid isused as the acid for the transesterification of the 4-(C₁ -C₂)alkoxy-3-pyrrolin-2-one.
 3. Process according to claim 2 wherein thetransesterification of the 4-(C₁ -C₂) alkoxy-3pyrrolin-2-one isperformed at a temperatures of 60° to 100° C. at a reduced pressure. 4.Process according to claim 1 wherein the reaction of the4-benzyloxy-3-pyrrolin-2-on-1-yl acetic acid (C₁ -C₄) alkyl ester withammonia takes place at a temperature of 60° to 80° C. in an autoclave.5. Process according to claim 1 wherein the transesterification of the4-(C₁ -C₂) alkoxy-3-pyrrolin-2-one is performed at a temperatures of 60°to 100° C. at a reduced pressure.
 6. Process according to claim 1wherein the 4-benzyloxy-3-pyrrolin-2-on-1-yl acetic acid (C₁ -C₄) alkylester is fed, without isolation, to the reaction with ammonia. 7.Process according to claim 1 wherein the reaction of the4-benzyloxy-3-pyrrolin-2-on-1-yl acetic acid (C₁ -C₄) alkyl ester withammonia takes place at a temperature of 60° to 80° C. in an autoclave.8. Process according to claim 1 wherein a sulfonic acid is used as acidfor the transesterification of the 4-(C₁-C₂)-alkoxy-3-pyrrolin-2-on-1-yl acetic acid (C₁ -C₄) alkyl ester. 9.Process according to claim 8 wherein the transesterification of the4-(C₁ -C₂) 4-alkoxy-3-pyrrolin-2-on-1-yl acetic acid (C₁ -C₄) alkylester is performed at a temperature of 80° to 120° C. under reducedpressure.
 10. Process according to claim 1 wherein thetransesterification of the 4-(C₁ -C₂) alkoxy-3-pyrrolin-2-on-1-yl aceticacid (C₁ -C₄) alkyl ester is is performed at a temperatures of 80° to120° C. under reduced pressure.
 11. Process according to claim 1 whereinthe reaction of the 4-benzyloxy-3-pyrrolin-2-on-1-yl acetic acid benzylester takes place, without its isolation, with ammonia at a temperatureof 60° to 80° C. in an autoclave.